Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

Edgar A. Otto; Toby W. Hurd; Rannar Airik; Moumita Chaki; Weibin Zhou; Corinne Stoetzel; Suresh B. Patil; Shawn Levy; Amiya K. Ghosh; Carlos A. Murga-Zamalloa; Jeroen Van Reeuwijk; Stef J.F. Letteboer; Liyun Sang; Rachel H. Giles; Qin Liu; Karlien L.M. Coene; Alejandro Estrada-Cuzcano; Rob W.J. Collin; Heather M. McLaughlin; Susanne Held; Jennifer M. Kasanuki; Gokul Ramaswami; Jinny Conte; Irma Lopez; Joseph Washburn; James MacDonald; Jinghua Hu; Yukiko Yamashita; Eamonn R. Maher; Lisa M. Guay-Woodford; Hartmut P.H. Neumann; Nicholas Obermüller; Robert K. Koenekoop; Carsten Bergmann; Xiaoshu Bei; Richard A. Lewis; Nicholas Katsanis; Vanda Lopes; David S. Williams; Robert H. Lyons; Chi V. Dang; Daniela A. Brito; M'nica Bettencourt Dias; Xinmin Zhang; James D. Cavalcoli; Gudrun Nürnberg; Peter Nürnberg; Eric A. Pierce; Peter K. Jackson; Corinne Antignac; Sophie Saunier; Ronald Roepman; Helene Dollfus; Hemant Khanna; Friedhelm Hildebrandt

doi:10.1038/ng.662

Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

Edgar A. Otto, Toby W. Hurd, Rannar Airik, Moumita Chaki, Weibin Zhou, Corinne Stoetzel, Suresh B. Patil, Shawn Levy, Amiya K. Ghosh, Carlos A. Murga-Zamalloa, Jeroen Van Reeuwijk, Stef J.F. Letteboer, Liyun Sang, Rachel H. Giles, Qin Liu, Karlien L.M. Coene, Alejandro Estrada-Cuzcano, Rob W.J. Collin, Heather M. McLaughlin, Susanne HeldJennifer M. Kasanuki, Gokul Ramaswami, Jinny Conte, Irma Lopez, Joseph Washburn, James MacDonald, Jinghua Hu, Yukiko Yamashita, Eamonn R. Maher, Lisa M. Guay-Woodford, Hartmut P.H. Neumann, Nicholas Obermüller, Robert K. Koenekoop, Carsten Bergmann, Xiaoshu Bei, Richard A. Lewis, Nicholas Katsanis, Vanda Lopes, David S. Williams, Robert H. Lyons, Chi V. Dang, Daniela A. Brito, M'nica Bettencourt Dias, Xinmin Zhang, James D. Cavalcoli, Gudrun Nürnberg, Peter Nürnberg, Eric A. Pierce, Peter K. Jackson, Corinne Antignac, Sophie Saunier, Ronald Roepman, Helene Dollfus, Hemant Khanna, Friedhelm Hildebrandt

Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

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Abstract

Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

Original language	English (US)
Pages (from-to)	840-850
Number of pages	11
Journal	Nature Genetics
Volume	42
Issue number	10
DOIs	https://doi.org/10.1038/ng.662
State	Published - Oct 2010

ASJC Scopus subject areas

Genetics

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Otto, E. A., Hurd, T. W., Airik, R., Chaki, M., Zhou, W., Stoetzel, C., Patil, S. B., Levy, S., Ghosh, A. K., Murga-Zamalloa, C. A., Van Reeuwijk, J., Letteboer, S. J. F., Sang, L., Giles, R. H., Liu, Q., Coene, K. L. M., Estrada-Cuzcano, A., Collin, R. W. J., McLaughlin, H. M., ... Hildebrandt, F. (2010). Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy. Nature Genetics, 42(10), 840-850. https://doi.org/10.1038/ng.662

Otto, EA, Hurd, TW, Airik, R, Chaki, M, Zhou, W, Stoetzel, C, Patil, SB, Levy, S, Ghosh, AK, Murga-Zamalloa, CA, Van Reeuwijk, J, Letteboer, SJF, Sang, L, Giles, RH, Liu, Q, Coene, KLM, Estrada-Cuzcano, A, Collin, RWJ, McLaughlin, HM, Held, S, Kasanuki, JM, Ramaswami, G, Conte, J, Lopez, I, Washburn, J, MacDonald, J, Hu, J, Yamashita, Y, Maher, ER, Guay-Woodford, LM, Neumann, HPH, Obermüller, N, Koenekoop, RK, Bergmann, C, Bei, X, Lewis, RA, Katsanis, N, Lopes, V, Williams, DS, Lyons, RH, Dang, CV, Brito, DA, Dias, MB, Zhang, X, Cavalcoli, JD, Nürnberg, G, Nürnberg, P, Pierce, EA, Jackson, PK, Antignac, C, Saunier, S, Roepman, R, Dollfus, H, Khanna, H & Hildebrandt, F 2010, 'Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy', Nature Genetics, vol. 42, no. 10, pp. 840-850. https://doi.org/10.1038/ng.662

@article{dd72cb7f1e764401944233cc697c3cf5,

title = "Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy",

abstract = "Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.",

author = "Otto, {Edgar A.} and Hurd, {Toby W.} and Rannar Airik and Moumita Chaki and Weibin Zhou and Corinne Stoetzel and Patil, {Suresh B.} and Shawn Levy and Ghosh, {Amiya K.} and Murga-Zamalloa, {Carlos A.} and {Van Reeuwijk}, Jeroen and Letteboer, {Stef J.F.} and Liyun Sang and Giles, {Rachel H.} and Qin Liu and Coene, {Karlien L.M.} and Alejandro Estrada-Cuzcano and Collin, {Rob W.J.} and McLaughlin, {Heather M.} and Susanne Held and Kasanuki, {Jennifer M.} and Gokul Ramaswami and Jinny Conte and Irma Lopez and Joseph Washburn and James MacDonald and Jinghua Hu and Yukiko Yamashita and Maher, {Eamonn R.} and Guay-Woodford, {Lisa M.} and Neumann, {Hartmut P.H.} and Nicholas Oberm{\"u}ller and Koenekoop, {Robert K.} and Carsten Bergmann and Xiaoshu Bei and Lewis, {Richard A.} and Nicholas Katsanis and Vanda Lopes and Williams, {David S.} and Lyons, {Robert H.} and Dang, {Chi V.} and Brito, {Daniela A.} and Dias, {M'nica Bettencourt} and Xinmin Zhang and Cavalcoli, {James D.} and Gudrun N{\"u}rnberg and Peter N{\"u}rnberg and Pierce, {Eric A.} and Jackson, {Peter K.} and Corinne Antignac and Sophie Saunier and Ronald Roepman and Helene Dollfus and Hemant Khanna and Friedhelm Hildebrandt",

note = "Funding Information: We thank families and study subjects for their contributions and E. Nigg for the OFD1 antibody. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to H.K. (EY007961), to D.S.W. (EY13408), to N.K. (HD042601, DK075972, DK072301) and to E.A.P. (EY12910); by grants from the Netherlands Organization for Scientific Research to K.L.M.C. (NWO Toptalent-021.001.014), to R.R. (NWO Vidi-91786396) and to R.H.G. (NWO Vidi-917.66.354); by the WellChild and Wellcome Trust to E.R.M.; by the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et D{\'e}ficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007 and the Association Bardet-Biedl, France to H.D., C.S. and E.A.P. by the Foundation Fighting Blindness, the Research to Prevent Blindness, the F.M. Kirby Foundation and the Rosanne Silbermann Foundation to E.A.P.; by the Midwest Eye Banks and Transplantation Center and Rare Disease Initiative, University of Michigan to H.K.; by Instituto Gulbenkian de Ci{\^e}ncia and EMBO to M.B.D.; by the Deutsche Nierenstiftung, PKD Foundation and DFG (BE 3910/5-1 and SFB/TRR57) to C.B.; by CIHR, FFB-Canada, FRSQ and Reseau Vision to R.K.K.; by the “Else Kr{\"o}ner-Fresenius-Stiftung” (P66/09//A75/09) to H.P.H.N.; and by EU FP7 Consortium “SYSCILIA” to R.H.G., R.R. and N.K. F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick G. L. Huetwell Professor. D.S.W. is a Jules and Doris Stein RPB professor. N.K. is a George R. Brumley Professor. S.S. is a laureate of the Equipe FRM (Dequation (20071210558)) and the Agence National de la Recherche (R07089KS). We thank the physicians who contributed to this study; A. Toutain, M.-C. Gubler, R. Salomon, M.-A. Macher and M. Fischbach for clinical data; S.J. Allen, A. Saveliev and Y. Liu for technical assistance; K. Tory and C. Becker for linkage analysis and exon sequencing; S. Shi and R. Insolera for shRNA clones; C. Janke for the GT335 antibody; J. Salisbury for the centrin-2 antibody; E. Nigg for the CEP164 antibody; and B. Chang for the CEP290 antibody.",

year = "2010",

month = oct,

doi = "10.1038/ng.662",

language = "English (US)",

volume = "42",

pages = "840--850",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "10",

}

TY - JOUR

T1 - Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

AU - Otto, Edgar A.

AU - Hurd, Toby W.

AU - Airik, Rannar

AU - Chaki, Moumita

AU - Zhou, Weibin

AU - Stoetzel, Corinne

AU - Patil, Suresh B.

AU - Levy, Shawn

AU - Ghosh, Amiya K.

AU - Murga-Zamalloa, Carlos A.

AU - Van Reeuwijk, Jeroen

AU - Letteboer, Stef J.F.

AU - Sang, Liyun

AU - Giles, Rachel H.

AU - Liu, Qin

AU - Coene, Karlien L.M.

AU - Estrada-Cuzcano, Alejandro

AU - Collin, Rob W.J.

AU - McLaughlin, Heather M.

AU - Held, Susanne

AU - Kasanuki, Jennifer M.

AU - Ramaswami, Gokul

AU - Conte, Jinny

AU - Lopez, Irma

AU - Washburn, Joseph

AU - MacDonald, James

AU - Hu, Jinghua

AU - Yamashita, Yukiko

AU - Maher, Eamonn R.

AU - Guay-Woodford, Lisa M.

AU - Neumann, Hartmut P.H.

AU - Obermüller, Nicholas

AU - Koenekoop, Robert K.

AU - Bergmann, Carsten

AU - Bei, Xiaoshu

AU - Lewis, Richard A.

AU - Katsanis, Nicholas

AU - Lopes, Vanda

AU - Williams, David S.

AU - Lyons, Robert H.

AU - Dang, Chi V.

AU - Brito, Daniela A.

AU - Dias, M'nica Bettencourt

AU - Zhang, Xinmin

AU - Cavalcoli, James D.

AU - Nürnberg, Gudrun

AU - Nürnberg, Peter

AU - Pierce, Eric A.

AU - Jackson, Peter K.

AU - Antignac, Corinne

AU - Saunier, Sophie

AU - Roepman, Ronald

AU - Dollfus, Helene

AU - Khanna, Hemant

AU - Hildebrandt, Friedhelm

N1 - Funding Information: We thank families and study subjects for their contributions and E. Nigg for the OFD1 antibody. This research was supported by grants from the National Institutes of Health to F.H. (DK1069274, DK1068306, DK064614), to H.K. (EY007961), to D.S.W. (EY13408), to N.K. (HD042601, DK075972, DK072301) and to E.A.P. (EY12910); by grants from the Netherlands Organization for Scientific Research to K.L.M.C. (NWO Toptalent-021.001.014), to R.R. (NWO Vidi-91786396) and to R.H.G. (NWO Vidi-917.66.354); by the WellChild and Wellcome Trust to E.R.M.; by the Avenir-INSERM program, the Agence Nationale pour la Recherche, the Union Nationale pour les Aveugles et Déficients Visuels, RETINA France, Programme Hospitalier de Recherche National 2007 and the Association Bardet-Biedl, France to H.D., C.S. and E.A.P. by the Foundation Fighting Blindness, the Research to Prevent Blindness, the F.M. Kirby Foundation and the Rosanne Silbermann Foundation to E.A.P.; by the Midwest Eye Banks and Transplantation Center and Rare Disease Initiative, University of Michigan to H.K.; by Instituto Gulbenkian de Ciência and EMBO to M.B.D.; by the Deutsche Nierenstiftung, PKD Foundation and DFG (BE 3910/5-1 and SFB/TRR57) to C.B.; by CIHR, FFB-Canada, FRSQ and Reseau Vision to R.K.K.; by the “Else Kröner-Fresenius-Stiftung” (P66/09//A75/09) to H.P.H.N.; and by EU FP7 Consortium “SYSCILIA” to R.H.G., R.R. and N.K. F.H. is an Investigator of the Howard Hughes Medical Institute, a Doris Duke Distinguished Clinical Scientist and a Frederick G. L. Huetwell Professor. D.S.W. is a Jules and Doris Stein RPB professor. N.K. is a George R. Brumley Professor. S.S. is a laureate of the Equipe FRM (Dequation (20071210558)) and the Agence National de la Recherche (R07089KS). We thank the physicians who contributed to this study; A. Toutain, M.-C. Gubler, R. Salomon, M.-A. Macher and M. Fischbach for clinical data; S.J. Allen, A. Saveliev and Y. Liu for technical assistance; K. Tory and C. Becker for linkage analysis and exon sequencing; S. Shi and R. Insolera for shRNA clones; C. Janke for the GT335 antibody; J. Salisbury for the centrin-2 antibody; E. Nigg for the CEP164 antibody; and B. Chang for the CEP290 antibody.

PY - 2010/10

Y1 - 2010/10

N2 - Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

AB - Nephronophthisis-related ciliopathies (NPHP-RC) are recessive disorders that feature dysplasia or degeneration occurring preferentially in the kidney, retina and cerebellum. Here we combined homozygosity mapping with candidate gene analysis by performing 'ciliopathy candidate exome capture' followed by massively parallel sequencing. We identified 12 different truncating mutations of SDCCAG8 (serologically defined colon cancer antigen 8, also known as CCCAP) in 10 families affected by NPHP-RC. We show that SDCCAG8 is localized at both centrioles and interacts directly with OFD1 (oral-facial-digital syndrome 1), which is associated with NPHP-RC. Depletion of sdccag8 causes kidney cysts and a body axis defect in zebrafish and induces cell polarity defects in three-dimensional renal cell cultures. This work identifies loss of SDCCAG8 function as a cause of a retinal-renal ciliopathy and validates exome capture analysis for broadly heterogeneous single-gene disorders.

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DO - 10.1038/ng.662

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JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

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